Neuroprotective Effects of Metformin on Cerebral Ischemia-Reperfusion Injury: Modulation of JNK and p38 MAP Kinase Signaling Pathways

Abstract Background: Cerebral ischemia-reperfusion injury (CIRI) is a common pathological process in stroke, associated with neuronal cell death and neurological dysfunction. Metformin, a widely used antidiabetic drug, has been found to possess various neuroprotective effects. However, its protective role in CIRI and the underlying mechanisms remain unclear. Objective: The present study aimed to investigate the neuroprotective effects of metformin on CIRI and the potential mechanisms by which it may modulate the c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38) signaling pathways. Methods: The impact of metformin on CIRI was assessed by establishing in vitro neuronal cell models of oxygen-glucose deprivation/reperfusion (OGD/R) and in vivo mouse models of middle cerebral artery occlusion (MCAO). Cell viability was evaluated using Cell Counting Kit-8 (CCK-8); protein expression levels were analyzed by Western Blot (WB); and cell apoptosis was detected by flow cytometry. The brain injury area in the animal model was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining; the activation status of JNK and p38 was detected by WB and phospho-JNK (p-JNK) immunofluorescence staining. Results: In vitro experiments demonstrated that metformin significantly eHT22nced the viability of cells exposed to OGD/R, reduced apoptosis, and inhibited the phosphorylation of JNK and p38 induced by OGD/R. In vivo experiments showed that metformin treatment significantly reduced the brain injury volume in MCAO mice and inhibited the expression of p-p38 and p-JNK. Additionally, neurological functions were improved in the metformin-treated group.